title: Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy.
abstract: OBJECTIVE
  Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta).
  
  
  METHODS
  Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3+3 phase Ib/II study design.
  
  
  RESULTS
  Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD; 3.6 mg/kg every 3 weeks) with standard dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clinical activity.
  
  
  CONCLUSIONS
  Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy.
authors.affiliation: Authors' Affiliations: Research Oncology, Departments of Biostatistics, Product Development Oncology, and Translational Oncology, Genentech, Inc., South San Francisco, California; Indiana University Simon Cancer Center, Indianapolis, Indiana; Institute Gustave Roussy, Villejuif; Department of Medical Oncology, Institut Curie, Paris, France; Sarah Cannon Research Institute, Nashville, Tennessee; Loyola University Medical Center, Maywood, Illinois; University of Munich, Munich, Germany; and Division of Medical Oncology, Centro di Riferimento Oncologico, Instituto Nazionale Tumori Aviano, Italy.
authors.forename: Gail D Lewis
authors.initials: GD
authors.lastname: Phillips
authors.forename: Carter T
authors.initials: CT
authors.lastname: Fields
authors.forename: Guangmin
authors.initials: G
authors.lastname: Li
authors.forename: Donald
authors.initials: D
authors.lastname: Dowbenko
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Kathy
authors.initials: K
authors.lastname: Miller
authors.forename: Fabrice
authors.initials: F
authors.lastname: Andre
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Veronique
authors.initials: V
authors.lastname: Dieras
authors.forename: Diana
authors.initials: D
authors.lastname: Crivellari
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Ellie
authors.initials: E
authors.lastname: Guardino
authors.forename: Steven R
authors.initials: SR
authors.lastname: Olsen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Crocker
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D019898:Autocrine Communication / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D051379:Mice; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors; D020880:Neuregulins / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction; D000068878:Trastuzumab; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020890:Neuregulin-1; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C485206:pertuzumab